Transport of meprin subunits through the secretory pathway: Role of the transmembrane and cytoplasmic domains and oligomerization

Jeremy A. Hengst, Judith S. Bond

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17 Scopus citations


The meprin α subunit, a multidomain metalloproteinase, is synthesized as a type I membrane protein and proteolytically cleaved during biosynthesis in the endoplasmic reticulum (ER), consequently losing its membrane attachment and COOH-terminal domains. The meprin α subunit is secreted as a disulfide-linked dimer that forms higher oligomers. By contrast, the evolutionarily related meprin β subunit retains the COOH-terminal domains during biosynthesis and travels to the plasma membrane as a disulfide-linked integral membrane dimer. Deletion of a unique 58-amino acid inserted domain (the I domain) of meprin α prevents COOH-terminal proteolytic processing and results in the retention of this subunit within the ER. To determine elements responsible for this retention versus transport to the cell surface, mutagenesis experiments were performed. Replacement of the meprin α transmembrane (αT) and cytoplasmic (αC) domains with their β counterparts allowed rapid movement of the α subunit to the cell surface. The meprin αT and αC domains substituted into meprin β delayed movement of this chimera through the secretory pathway. Replacement of glycines in the meprin αT domain GXXXG motif with leucine residues, alanine insertions in the meprin αT domain, and mutagenesis of basic residues within the meprin αC domain did not enhance the movement of the α subunit through the secretory pathway. By contrast, a mutant of meprin α (C320AαΔ I) that did not form disulfide-linked dimers or higher order oligomers was transported through the secretory pathway, although more slowly than meprin β. Taken together, the data indicate that the meprin αT and αC domains together contain a weak signal for retention within the ER/cis-Golgi compartments that is strengthened by oligomerization.

Original languageEnglish (US)
Pages (from-to)34856-34864
Number of pages9
JournalJournal of Biological Chemistry
Issue number33
StatePublished - Aug 13 2004

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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